Administration of Antenatal Corticosteroids: Current State of Knowledge

The administration of a single course of corticosteroids before week 34 + 0 of gestation in cases with impending preterm birth is now standard procedure in obstetric care and firmly established in the guidelines of different countries. But despite the apparently convincing data, numerous aspects of this intervention have not yet been properly studied. It is still not clear which corticosteroid achieves the best results. There are very few studies on what constitutes an appropriate dose, circadian rhythms, the time frame in which corticosteroids are effective, and the balance between the risks and benefits of repeat administration. As the existing studies have rarely included patients before week 24 + 0 of gestation, we have very little information on the possible benefits of administering corticosteroids before this timepoint. If corticosteroids are administered antenatally after week 34 + 0 of gestation, the short-term benefit may be offset by the long-term adverse effect on psychomotor development. This present study summarizes the current state of knowledge regarding these issues.

The association between albumin-globulin ratio (AGR) and survival in patients treated with immune checkpoint inhibitors

BACKGROUND: The albumin-globulin ratio (AGR) could be a prognostic biomarker in patients with cancer, although the data is limited in patients treated with immune-checkpoint inhibitors (ICIs). OBJECTIVES: We aimed to evaluate the association between AGR and survival in ICI-treated patients. METHODS: The data of 212 advanced-stage patients were retrospectively evaluated in this cohort study. The association between AGR with overall (OS) and progression-free survival (PFS) were evaluated with multivariate analyses. Additionally, receptor operating curve (ROC) analysis was conducted to assess the AGR’s predictive power in the very early progression (progression within two months) and long-term benefit (more than twelve months survival). RESULTS: The median AGR was calculated as 1.21, and patients were classified into AGR-low and high subgroups according to the median. In the multivariate analyses, patients with lower AGR (< 1.21) had decreased OS (HR: 1.530, 95% CI: 1.100–2.127, p= 0.011) and PFS (HR: 1.390, 95% CI: 1.020–1.895, p= 0.037). The area under curve of AGR to detect early progression and long-term benefit were 0.654 (95% CI: 0.562–0.747, p= 0.001) and 0.671 (95% CI: 0.598–0.744, p< 0.001), respectively. CONCLUSIONS: In our experience, survival with ICIs was impaired in patients with lower AGR. Additionally, the AGR values could detect the very early progression and long-term benefit ICIs.

Follicular Lymphoma Microenvironment Signatures Define Patients Subsets Obtaining Long Term Clinical Benefit after Single-Agent First-Line Anti-CD20 Immunotherapy

The role of first-line single agent Rituximab immunotherapy in follicular lymphoma (FL) is still a matter of debate. Although a subset of patients (pts) may obtain long term benefit with upfront immunotherapy, first-line therapy with standard chemoimmunotherapy offers better results in terms of progression free survival (PFS) compared to single agent Rituximab. On the other hand, there is no clear demonstration of sizeable long term benefit with first-line Rituximab compared to an initial wait and see approach, as most FL pts will ultimately be exposed to chemotherapy at some point in their disease course. Here we show that the efficacy of front line anti CD20 immunotherapy in FL could be dependent on microenvironmental factors, and that specific immune signatures could define FL pts subsets obtaining maximal benefit from upfront anti CD20 immunotherapy. First, we retrospectively analyzed the outcome of our single center cohort of 81 FL pts treated with first-line single agent Rituximab therapy with (n=53) or without (n=28) maintenance. The vast majority of pts considered in this analysis were treated in the context of several clinical trials exploring the efficacy of upfront single agent originator (SAKK 35/98, 35/03, 35/10: n= 68) or biosimilar (JASMINE and REFLECTIONS B328/06 n= 9) Rituximab, which were ran at our center from 2000 to 2018. Four patients received off-label single agent Rituximab. Median age was 55 years (y), 52% (42) of patients were female, 72% (58) stage III-IV, 76% (62) were Follicular international prognostic index (FLIPI) score 0-2, 26% (21) were bulky, 52% (42) were high tumor burden according to the GELF criteria. After a median follow-up of 9.5 y, the overall survival (OS) and PFS rates were 82% and 35% respectively. With a long follow-up, these data are in line with previous findings indicating that a sizeable fraction of FL pts derive long term benefit from upfront single agent Rituximab maintaining a continuous complete remission. Paraffin embedded tissue from initial diagnosis was available in 39 pts. In order to dissect determinants of Rituximab immunotherapy efficacy in this homogeneous chemo-naive population, we analyzed FL diagnostic biopsies (n=39 FL + 5 healthy controls) with targeted gene expression profiling (T-GEP) on the NanoString platform, using the PanCancer Immune Profiling panel, which includes 730 genes belonging to the most relevant immunologic checkpoints and pathways. A 20-gene signature including genes involved in chemokine-cytokine signaling, T-regulatory cells, natural-killer cell activity and interleukin-17 signaling was significantly associated with the achievement of a complete response after induction +/- maintenance treatment. A simple 6-gene immune signature (hereafter ImSig) was found to be significantly associated with PFS, with IL22RA2, CCL22, TNFRSF4, IL17RB, CCL19 overexpression and CD209 downregulation being associated with worse outcome. By applying the maxstat package 10-y PFS was 65% for ImSig low pts vs 6% for ImSig high pts (p&lt;0.0001). In multivariate analysis only the 6-gene ImSig and Rituximab maintenance retained independent prognostic value (p&lt;0.001 and 0.002 respectively). As opposite, GELF criteria (present/absent = 27/12) and FLIPI score (0-2/3-5 = 23/16) were not associated with PFS. The 6-gene immune signature was validated in silico in 2 independent publicly available cohorts of FL pts treated with upfront chemoimmunotherapy: a cohort of 137 pts (Silva et al 2019, Affimetryx platform) and a cohort of 50 pts (Bararia et al. 2020), the latter analyzed on the NanoString Platform with the same T-GEP panel (PanCancer Immune Profiling) used in our discovery cohort. The 6-gene signature was confirmed to be a powerful outcome predictor in these 2 chemoimmunotherapy-treated cohorts, and notably the 10-y PFS rates of ImSig low vs high patients mirrored the results observed with single agent immunotherapy in the discovery cohort. The results here reported indicate that pts with a favorable immune signature could derive maximal benefit from a first-line chemo-free treatment approach with single agent Rituximab, achieving and maintaining complete remission in the long term, irrespective of the tumor burden and other clinical variables. Thus, profiling of FL microenvironment with T-GEP could provide a useful tool for selecting patients who may be suitable for a chemo-free upfront treatment with anti CD20 immunotherapy. Disclosures Derenzini: TG-THERAPEUTICS: Research Funding; ASTRA-ZENECA: Consultancy, Other: ADVISORY-BOARD; ADC-THERAPEUTICS: Research Funding; TAKEDA: Research Funding; BEIGENE: Other: ADVISORY BOARD. Pileri: CELGENE: Other: ADVISORY BOARD; NANOSTRING: Other: ADVISORY BOARD; ROCHE: Other: ADVISORY-BOARD. Tarella: ADC-THERAPEUTICS: Other: ADVISORY BOARD; Abbvie: Other: ADVISORY BOARD. OffLabel Disclosure: First line single agent Rituximab in Follicular Lymphoma

Response Rate, Event-Free Survival (EFS) and Overall Survival (OS) in Higher-Risk Myelodysplastic Syndromes (HR-MDS): U.S. Food and Drug Administration (FDA) Patient-Level Analyses

Background: Hypomethylating agents (HMAs) have changed the treatment landscape for patients with higher-risk myelodysplastic syndromes (HR-MDS) in the past two decades. However, less than half of patients respond to HMA therapy and even the best responses are transient and non-curative. Therapeutic options for those who have failed HMAs are limited, and these patients have very poor prognosis. To speed the development of novel therapeutics, varying response rate definitions and event-free survival (EFS) have been suggested as clinical benefit endpoints for regulatory approvals. However, the relationship between complete remission (CR), partial remission (PR), hematologic improvement (HI), event-free survival (EFS) and overall survival (OS) in MDS has not been conclusively established. To evaluate the relationship between these endpoints, we conducted patient-level response analyses of MDS trials submitted to the FDA. Methods: We searched for trials submitted with New Drug Applications for treatment of MDS between 2000 and 2020. Trials which supported the efficacy of approved treatments for HR-MDS were included. Patients with chronic myelomonocytic leukemia (CMML), bone marrow blasts ≥ 20%, or missing bone marrow blast information were excluded. A patient-level responder analysis was performed to compare OS and EFS between responders and non-responders, regardless of treatment assignment in the pooled dataset. Separate analyses were formed for CR, PR, and HI. Response rates were defined per protocol; criteria included IWG 2000, IWG 2006, and custom criteria. EFS was defined as time from randomization, or first dose of study drug for single-arm trials, to treatment failure (defined as date of transformation to AML, given availability across trials) or death from any cause. For each trial, the hazard ratio of response vs. no-response on OS and EFS was estimated using a Cox model with response as a time-varying covariate and treatment, sex, age, and percentage blast count as baseline covariates. The resulting hazard ratios were combined assuming a common effect of response on clinical outcome to estimate a pooled hazard ratio. Unadjusted distributions of OS and EFS by response were obtained using the Kaplan-Meier method. Results: We identified 8 trials with a total of 772 patients with HR-MDS investigating 3 experimental agents (azacitidine, decitabine, and decitabine + cedazuridine) for the treatment of HR-MDS. Three trials were randomized trials to assess efficacy (N=116, 124, 215), two were randomized crossover trials to assess bioequivalence (N=116, 61), and 3 were single arm trials (N=29, 34, 77). Across all trials, the population characteristics were: median age 69 years (range: 23-92); 70% male, 67% White, 29% Asian, 2% Black; 17% High Risk per IPSS, 25% Intermediate-1, 33% Intermediate-2, 2% Low Risk, and 24% unknown. IPSS information was missing for 3 trials (187 patients). We assessed the effect of CR vs. PR vs. HI in a pooled analysis. Patients who achieved a CR had better OS (HR=0.40 [95% CI: 0.25-0.64]) and EFS (HR=0.39 [95% CI: 0.24-0.63]) compared with non-responders, defined as patients who failed to achieve CR, PR, or HI. Patients who achieved a PR had better OS (HR=0.51 [95% CI: 0.28-0.92]) and EFS (HR=0.66 [95% CI: 0.37-1.17]) compared to non-responders. Patients who achieved an HI response had better OS (HR=0.60 [95% CI: 0.46-0.76]) and EFS (HR=0.60 [95% CI: 0.47-0.76]) compared to non-responders. Patients who achieved a CR+PR had a trend for longer OS (HR=0.73 [95% CI: 0.49-1.11]) and EFS (HR=0.76 [95% CI: 0.51-1.14]) compared with those who achieved HI alone. Between-study variances of these effects were not able to be reliably estimated due to the low number of responses per trial and low number of trials included in the analysis. Figures 1 and 2 present unadjusted Kaplan-Meier estimates of OS and EFS by response group. Conclusions: Patient-level responder analyses suggest that CR, PR, and HI responders have better OS and EFS compared with non-responders. A limitation of these analyses is that response criteria are not standardized across trials. Future work includes standardizing response criteria across trials. However, our results suggest that CR, PR, and HI may be associated with long-term benefit in patients with HR-MDS. While HI responses had better OS compared to no response, CR and CR+PR remain the response endpoints associated with greatest long-term benefit. Figure 1 Figure 1. Disclosures Vallejo: AstraZeneca: Other: Spouse is employed by AstraZeneca..

Connectivity-based thalamus parcellation and surgical targeting of somatosensory subnuclei

OBJECTIVE The anatomy of the posterolateral thalamus varies substantially between individuals, presenting a challenge for surgical targeting. Patient-specific, connectivity-based parcellation of the thalamus may effectively approximate the ventrocaudal nucleus (Vc). This remains to be robustly validated or assessed as a method to guide surgical targeting. The authors assessed the validity of connectivity-based parcellation for targeting the Vc and its potential for improving clinical outcomes of pain surgery. METHODS A cohort of 19 patients with regional, chronic neuropathic pain underwent preoperative structural and diffusion MRI, then progressed to deep brain stimulation targeting the Vc based on traditional atlas coordinates. Surgical thalami were retrospectively segmented and then parcellated based on tractography estimates of thalamocortical connectivity. The location of each patient’s electrode array was analyzed with respect to their primary somatosensory cortex (S1) parcel and compared across patients with reference to the thalamic homunculus. RESULTS Ten patients achieved long-term pain relief. Sixty-one percent of an average array (interquartile range 42%–74%) was located in the S1 parcel. In patients who achieved long-term benefit from surgery, array location in the individually generated S1 parcels was medial for face pain, centromedial for arm pain, and centrolateral for leg pain. Patients who did not benefit from surgery did not follow this pattern. Standard stereotactic coordinates of electrode locations diverged from this pattern. CONCLUSIONS Connectivity-based parcellation of the thalamus appears to be a reliable method for segmenting the Vc. Identifying the Vc in this way, and targeting mediolaterally as appropriate for the region of pain, merits exploration in an effort to increase the yield of successful surgical procedures.

The use of GnRH analogs in preserving ovarian function during chemotherapy

Background The literature has always been controversial on the use of gonadotropin-releasing hormone agonists in preserving fertility in women of childbearing age after chemotherapy; thereby, in this article, we will be discussing its use in preserving fertility. Main body of abstract When it comes to preserving fertility, it is crucial to consider all available options in this topic due to its very sensitive nature, thereby we have found that while a lot of trials favor the use of gonadotropin-releasing hormone agonists, the lack of proper follow-up and long-term trials renders its use highly debatable, and since the longest follow-up trial showed non-significant results, it also opens the floor for debate on whether this short-term benefit is worth adding another drug to the regimen or not. Short conclusion As described in this review, while the use of gonadotropin-releasing hormone agonists is beneficial in a lot of studies, the lack of long-term reports still makes its use debatable, thereby more trials should be done.

A Case Report of Pulsed Radiofrequency Plus Suboccipital Injection of the Greater Occipital Nerve: An Easier Target for Treatment of Cluster Headache

Introduction: In cluster headache, the efficacy of suboccipital steroid injection is notable within a few days, although few data are available about the duration of efficacy. A combination treatment, consisting of suboccipital steroid injection plus pulsed radiofrequency, could potentially lead to long-term benefit. Evidence about pulsed radiofrequency of the greater occipital nerve is lacking.Patients and Methods: We retrospectively describe a series of four cluster headache patients treated with suboccipital steroid injection plus pulsed radiofrequency of the greater occipital nerve.Results: All patients achieved a 50% reduction in attack frequency in the 7 days after the first treatment. Moreover, a long pain-free remission period up to 15 months was noted.Conclusion: Suboccipital steroid injection plus pulsed radiofrequency of the greater occipital nerve might have both acute and prophylactic effects in cluster headache. The greater occipital nerve is more accessible to pulsed radiofrequency than other targets.